Orthostatic intolerance (OI) is a syndrome characterized by adrenergic symptoms brought on by upright posture. Usually, there is a heart rate increase of at least 30 bpm on standing without significant orthostatic hypotension. Jacob et al., Circulation (1997). Females are disproportionately affected and patients usually present in the second to fourth decade of life. Low et al., Neurology (1995). This dysautonomic syndrome is quite common and may have been first described as Da Costa's syndrome more than 100 years ago. Jordan et al., Chin J. Physiol (1997); Novak et al., J Aut N Syst (1996); Streeten, Orthostatic Disorders of the Circulation: Mechanisms, Manifestations and Treatment (1987). It has been re-recognized over the years as soldiers heart, neurocirculatory asthenia, and mitral valve prolapse syndrome. It also bears many similarities to chronic fatigue syndrome. Because of the prominent feature of orthostatic tachycardia, postural tachycardia syndrome (POTS) is a current popular name. Rosen et al., Am J Med (1982).
These features and their improvement with salt and volume replacement are consistent with hypovolemia and a secondary sympathetic activation. However, most patients are not hypovolemic. Excessive venous pooling with upright posture, hypersensitivity of veins to alpha-adrenoreceptor agonists and decreased autonomic latencies in the lower extremities are consistent with partial autonomic denervation as another mechanism which could cause secondary sympathetic activation. However, increased heart rate, plasma norepinephrine and muscle sympathetic nerve activity (MSNA) even in the supine position coupled with widely oscillating heart rate with upright posture and disparities among heart rate, plasma norepinephrine and MSNA responses to upright tilt are more consistent with fundamentally disordered autonomic regulation. Novak et al., J Aut N Syst (1996); Furlan et al., Circulation (1998); Shannon et al., Circulation (1998); Puddu et al., Am Heart J (1983); Pasternac et al., Am J Med (1982); Coghlan et al., Am J Med (1979).
Thus far, most explanations of the physiological and biochemical abnormalities in OI have focused on alterations in norepinephrine release (i.e., compensatory, excessive, or disordered). Streeten et al., J Lab Clin Med (1988); Furlan et al., Circulation (1998); Novak et al., Stroke (1998). An alternative explanation is an abnormality in synaptic norepinephrine clearance. Approximately 80–90% of norepinephrine released into many synapses can be cleared by neuronal re-uptake via the presynaptic norepinephrine transporter (NET), while the remaining 10–20% spills over into the circulation or extraneuronal tissue, as disclosed by Esler et al., Physiol Rev (1990).
To date, attempts to identify a genetic basis within the NE transporter gene for OI or other NE transport impairment have not been undertaken. It is further noted that drugs inhibiting NET (e.g., cocaine, amphetamines, tricyclic antidepressants) cause features typical of OI (i.e., tachycardia, orthostatic symptoms, and elevated plasma catecholamines). Thus, exploration of impaired NET function, including exploration of a genetic basis for such impaired NET function, would provide important information about the biological and addictive effects of these drugs.
What is needed, then, is further characterization of the structure of the NE transporter gene generally and in OI patients. Since the NE transporter plays a pivotal role in norepinephrine uptake at the synaptic cleft, further characterization of the structure and role of the NE transporter gene would meet a long-felt need in the art for diagnostic and therapeutic methods associated with NE transporter-mediated biological functions.